Osteoporosis is caused by reduced bone mass, leading to weakening of the bone strength and an increased risk of bone fracture. The bone mass is controlled by the continuous bone resorption and bone formation processes. The peak bone mass is achieved at about 25 ages in healthy people, and decreases slowly with advancing age. Women generally have a lower bone mass than men, and the bone loss becomes increasing more pronounced after menopause. Ten million people are presumed to suffer from osteoporosis in U.S., and about thirty-four million people in the world have the problem of low bone mass, and they are under the risk of osteoporosis. Clinical studies showed that the death rate within two years from the appearance of symptoms of osteoporosis is currently about 12%, and many osteoporosis patients (about 30%) are faced to stay home due to bone fracture. Recently, the number of osteoporosis patients has increased due to the aging of global population, and accordingly, there has existed a need for developing an efficacious medicament for preventing and treating osteoporosis.
Bone is a living tissue which is composed of several different types of cells. In healthy individuals, the amount of bone removed or resorbed by the osteoclastic cells is compensated by new bone made by the osteoblastic cells. The overall bone formation and bone resorption occur to the extent of about 14% of bones over a year to maintain a steady bone mass, but for individuals suffering from a bone-resorbing disease, such balance cannot be achieved. In women, about 5% a year bone loss from the spine occurs after menopause. Such symptom has been attributed to estrogen deficiency associated with menopause. However, the question as to what mechanism is involved between the loss of estrogen and increased bone resorption remains unresolved.
In order to reduce the risk of bone fracture, various methods for maintaining or increasing the bone mass are currently used, by reducing the bone resorption rate, increasing the bone formation rate, or a combination thereof. As therapeutic agents for blocking bone resorption, integrin αvβ3 antagonists, cathepsin K inhibitors, and inhibitors against OPG/PANKL/RANK system have been investigated. Further, as therapeutic agents for enhancing the bone formation, parathyroid hormones and their derivatives structure have been reported. Exemplary therapeutic agents include new parathyroid hormonal products, calcium sensing receptor antagonists which regulate the secretion of parathyroid hormone, selective androgen receptor modulators (SARMs), growth hormone secretagogues, insulin-like growth elements, proteosome inhibitors, and statins.
The currently methods for treating bone loss generally involve the administration of compounds such as estrogen, bisphosphonates, calcitonin, and raloxifene. These compounds, however, are generally used for long-term treatments, and they induce undesirable side effects. Further, such treatments are typically directed to the activity of mature osteoclasts, rather than reducing their formation. For example, estrogen induces the apoptosis of osteoclasts, while calcitonin causes the osteoclasts to shrink and detach from the bone surface (Hughes et al., Nat. Med. 2:1132-1136, 1996; Jilka et al., Exp. Hematol. 23:500-506, 1995). Similarly, bisphosphonates reduce the osteoclast activity, change their morphology, and increase the apoptosis of osteoclasts (Parfitt et al., J. Bone Miner Res. 11:150-159, 1996; Suzuki et al., Endocrinology 137: 4685-4690, 1996).
Currently available therapeutic agents for treating osteoporosis include bisphosphonates, hormonal drugs, vitamin D and its analogues, calcitonin, and calcium. Representative bisphosphonates include alendronate (Merck Co., Ltd.), risedronate (Hoffman-La Roche Ltd.), zoledronate (Novartis AG; EP Patent No. 275,821), ibandronate (Hoffman-La Roche Ltd.; U.S. Pat. No. 4,942,157), and minodronate (Yamanouchi Pharmaceutical Co., Ltd.; EP Patent No. 354,806). Bisphosphonates, however, suffers from the problems of low absorption rates through the gastrointestinal tract (10% or less) and the tendency to cause esophagitis when the patients do not follow the complicated administration guidance. In particular, it has been reported that alendronate causes some side effects, e.g., gastrointestinal disorders and osteonecrosis of the jaw, besides the fact that long-term administration of bisphosphonates osteonecrosis. Accordingly, novel therapeutic agents for osteoporosis are required.
Exemplary hormonal drugs include raloxifene (Eli Lilly Co.), droloxyfene (Pfizer Inc.; EP Patent No. 54168), lasopoxifene (Pfizer Inc.; WO 97/16434), FC-1271 (homosmedical Co. and Orion Corp.; WO 96/07402), TES-424 (Ligand Co. and Weyers Co.; U.S. Pat. No. 5,948,755), and SERMs, which are at the stage of clinical studies. However, these drugs bring the risk of causing breast or uterine cancer, and accordingly, they are not suitable for use as a therapeutic agent for osteoporosis which requires a long-term administration.
Further, vitamin D and its analogues are expensive and its therapeutic efficacy for osteoporosis is not clearly established; calcitonin is relatively expensive and requires a complicated administration procedure; and calcium is effective only for the prevention of osteoporosis, having no therapeutic effect.